The intricate nature of tight junctions (TJs) in maintaining epithelial and endothelial barriers is a focal point in cellular biology and medical research. TJs are crucial not only for defining the boundary between the internal and external environments of multicellular organisms but also for regulating paracellular permeability and maintaining apicobasal polarity. They are involved in numerous physiological processes and pathological states, including various inflammatory conditions and cancer.
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Fig. 1 Overview of tight junctions (Takasawa A., et al. 2023).
Structure and Function of Tight Junctions
Composition and Molecular Complexes
TJs form the most apical component of the cell-cell adhesion machinery in epithelial and endothelial cells. They consist of transmembrane proteins such as claudins, occludin, tricellulin, and junctional adhesion molecules (JAMs), as well as peripheral membrane proteins like zona occludens (ZO)-1, -2, -3, and cingulin. These proteins interact with the cytoskeleton through F-actin and myosin II, thus contributing to the mechanical stability and dynamic regulation of the TJ complex.
The ZO proteins, with their three PDZ domains, mediate binding to other transmembrane tight junction proteins (TJPs), such as claudins, in a dynamic, energy-dependent manner. These proteins also serve as direct targets and effectors of various signaling pathways, such as the myosin light chain kinase pathway, thereby influencing the assembly, maintenance, and barrier function of TJs.
Function of Tight Junctions
TJs perform two major functions: the barrier function and the fence function. The barrier function is essential for regulating the paracellular permeability of ions, solutes, and low molecular weight molecules (< 600 kDa), while the fence function prevents the intermixing of apical and basolateral membrane components, thus maintaining cell polarity.
In the gut, for instance, the expression of claudins varies according to localization, contributing to the functional properties at specific sites. Claudin-2, found at the apical pole throughout the crypt-villus axis in the jejunum, contrasts with claudin-4, which is expressed throughout the crypt-villus axis in both the small and large intestines. These differences in distribution are thought to relate to cell differentiation, carbohydrate metabolism, and transcription factors like HNF1α, Cdx2, and GATA-4.
Tight Junctions in Health
In a healthy state, TJs construct a dynamic intestinal barrier that regulates the paracellular uptake of water, nutrients, and electrolytes. They may be size- and/or charge-selective and actively prevent contact between the basolateral and apical cell membranes. While some tight junction proteins enhance barrier formation, others form size- and/or charge-selective channels or pores.
Epithelial Barrier Function in Inflammatory Bowel Diseases
Pathogenesis and TJ Dysfunction
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), share a multifactorial etiology involving genetic susceptibility, environmental factors, and immune dysregulation. These diseases are characterized by intestinal inflammation that compromises the integrity of the epithelial barrier, leading to increased permeability and infiltration of pathogens.
Both CD and UC exhibit common pathological features such as epithelial breaks, reduction in tight junction strands, and glandular atrophy. In patients with clinically active CD, increased intestinal permeability is often observed. Barrier dysfunction in IBD is attributed to epithelial damage, including apoptosis, erosion, and ulceration, which are hallmarks of gut inflammation. Inflammatory cytokines, such as IL-13 in UC and IFN-γ in CD, further alter epithelial permeability by modulating junctional complexes.
Claudin Expression and IBD
Studies have shown varying patterns of claudin expression in IBD patients. For instance, claudin-2, known for forming pore-selective channels, is upregulated in both UC and CD, correlating with disease severity. Conversely, the expression of "tightening" claudins like claudin-3, -4, and -7 is often reduced in UC. These alterations in TJ protein expression are indicative of the disrupted epithelial barrier function in IBD.
In pouchitis, a condition associated with restorative proctocolectomy for UC increased epithelial permeability and bacterial translocation are observed. Elevated claudin-2 levels have been documented in acute pouchitis, suggesting an early role in the development of inflammation.
Therapeutic Implications
Strategic manipulation of TJs and intestinal permeability holds potential as a therapeutic avenue for IBD. Anti-TNF therapy, effective in treating CD and UC, has been shown to restore barrier function and modulate TJ protein expression. Novel compounds, such as butyrate, quercetin, and berberine, have demonstrated promise in enhancing epithelial barrier function by regulating TJ proteins.
Furthermore, probiotics and their derivatives have garnered attention for their role in TJ regulation. For instance, Lactobacilli have been shown to attenuate epithelial permeability and upregulate TJ protein expression in experimental colitis.
Tight Junctions and Cancer
Role in Cancer Progression
In the context of cancer, the epithelial-mesenchymal transition (EMT) is a well-recognized pathway driving tumor progression. EMT-related transcription factors like snail and slug induce a "cadherin switch" from epithelial-type E-cadherin to mesenchymal-type N-cadherin, perturbing adherens junctions (AJs) and TJs, leading to the loss of epithelial polarity. Decreased levels of TJ proteins (TJPs), such as occludin, have been noted as signs of malignant transformation in poorly differentiated tumors.
Claudin Expression and Cancer
The relationship between TJP expression and cancer is complex and tissue-dependent. For instance, claudin-3 and claudin-4 expression in ovarian cancer cells and decreased claudin-1 expression in lung adenocarcinoma cells have been linked to enhanced malignancy. However, recent studies indicate that the cancer-associated expression of TJPs is not always decreased; in some cases, it may be upregulated, contributing to the malignant potential of cancer cells.
Diagnostic and Therapeutic Potential
TJPs, due to their altered expression in cancers, have potential as diagnostic markers and therapeutic targets. For instance, claudin-4, claudin-7, and JAM-A are significantly increased in neoplastic lung adenocarcinomas compared to normal epithelial tissues. Similarly, claudin-1 and JAM-A are potential biomarkers for cervical adenocarcinoma, distinguishing neoplastic lesions from non-neoplastic tissues with high specificity and sensitivity.
In pancreatic adenocarcinoma and bile duct cancers, claudin-18.2 expression is significantly elevated in neoplastic regions, making it a candidate for early cancer detection. Additionally, antibodies targeting the extracellular domains of TJPs, such as anti-claudin-18.2 (zolbetuximab) for gastric cancer, are being evaluated in clinical trials, underscoring the therapeutic potential of these proteins.
Conclusion
Tight junctions play a pivotal role in maintaining epithelial and endothelial barriers, with significant implications for health and disease. In inflammatory bowel diseases, dysregulation of TJ proteins contributes to barrier dysfunction and inflammation, with therapeutic strategies targeting TJ modulation showing promise. In cancer, the altered expression of TJPs serves as both a diagnostic marker and a potential therapeutic target. Future research should focus on elucidating the molecular mechanisms underlying TJ regulation and leveraging this knowledge for innovative therapeutic approaches in managing IBD and cancer. Understanding the intricate balance of tight junction functions and their disruption in disease states will pave the way for novel diagnostic and therapeutic strategies aimed at improving patient outcomes.
References
- Takasawa A., et al. Emerging roles of transmembrane‐type tight junction proteins in cancers. Pathology International. 2023, 73(8): 331-340.
- Landy J., et al. Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer. World Journal of Gastroenterology. 2016, 22(11): 3117.
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